Outcomes of Rotigotine Clinical Tri a l s Effects on Motor and Nonmotor Symptoms of Parkinson’s Disease Kelly E. Lyons,
PhD*,
Rajesh Pahwa,
MD
KEYWORDS Rotigotine Parkinson’s disease Clinical trials Motor symptoms Nonmotor symptoms KEY POINTS Large, multicenter, randomized controlled trials have demonstrated the safety and efficacy of rotigotine 24-hour transdermal system for the treatment of motor symptoms associated with both early and advanced Parkinson’s disease (PD). In addition to the significant improvements in motor function and reductions in off-time, nonmotor symptoms, such as sleep, mood, and quality of life, were significantly improved with rotigotine. Adverse events (AEs) were typical of those seen with other dopamine agonists, with the most common AEs including application site reactions, nausea, dizziness, and somnolence. Rotigotine transdermal system is a safe and efficacious treatment option in patients with early PD as monotherapy and as adjunct to levodopa in patients with more advanced PD.
INTRODUCTION
Rotigotine (Neupro) is a nonergot dopamine agonist delivered through a 24-hour transdermal system. It is approved in the United States and multiple European countries as a treatment of both early and advanced PD. In the United States, for early Disclosures: Dr Lyons has received personal compensation from Adamas, St Jude Medical, and Teva Neuroscience. Dr Pahwa has received grants from National Institutes of Health, National Parkinson Foundation, Teva Neuroscience, Novartis, Xenoport, Impax, EMD Serono, Allon, Acadia, Schering, Biotie, Phytopharm, and Adamas. He has received personal compensation from Novartis, Teva Neuroscience, Medtronic, St Jude Medical, GE Healthcare, EMD Serono, Adamas, and Impax. This article was written entirely by Drs Lyons and Pahwa. The authors were compensated directly for medical writing/editorial support because any outside medical writing/editorial support was declined. Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Boulevard, MS 2012, Kansas City, KS 66160, USA * Corresponding author. E-mail address:
[email protected] Neurol Clin 31 (2013) S51–S59 http://dx.doi.org/10.1016/j.ncl.2013.04.011 neurologic.theclinics.com 0733-8619/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
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treatment, rotigotine is initiated at 2 mg/24 h and increased by 2-mg/24 h increments as needed to a maximum dose of 6 mg/24 h. For advanced treatment, rotigotine is initiated at 4 mg/24 h and increased by 2-mg/24 h increments as needed, up to a maximum dose of 8 mg/24 h. In European countries, the maximum approved dose for early disease is 8 mg/24 h and the maximum approved dose for advanced disease is 16 mg/24 h. For the treatment of PD, rotigotine is available in patch strengths of 2 mg/24 h (4.5 mg/d or 10 cm2), 4 mg/24 h (9 mg/d or 20 cm2), 6 mg/24 h (13.5 mg/d or 30 cm2), and 8 mg/24 h (18 mg/d or 40 cm2). Randomized, doubleblind, placebo-controlled trials have demonstrated the safety and efficacy of rotigotine in the treatment of both early and advanced motor symptoms and some nonmotor symptoms of PD. EARLY PARKINSON’S DISEASE TRIALS
The Parkinson Study Group1 conducted a placebo-controlled, double-blind study of 242 patients with early PD randomized to either placebo or daily rotigotine 2 mg/24 h (4.5 mg/d), 4 mg/24 h (9 mg/d), 6 mg/24 h (13.5 mg/d), or 8 mg/24 h (18 mg/d) for 11 weeks. The mean subject age was approximately 61 years and PD duration was approximately 1 year. The primary outcome variable, the Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living (ADL) plus motor score, was improved in each of the rotigotine groups compared with placebo. There was a dose response, however, and the only significant improvements were seen with the 6-mg/24 h and 8-mg/24 h doses (Table 1). AEs that were significantly more common with rotigotine than placebo were typical of a dopamine agonist and included nausea, somnolence, insomnia, vomiting, and fatigue (Table 2). The
Table 1 Demographics and treatment effects for the UPDRS ADL (part II) plus motor (part III) scores for randomized, double-blind, controlled trials of rotigotine in early Parkinson’s disease Ageb (y)
Disease Durationb (y)
Treatment Effect: UPDRS ADL D Motor
Study
Daily Dosage
n
Study Duration (wk)
Parkinson Study Group,1 2003
Rotigotine (2 mg/24 Rotigotine (4 mg/24 Rotigotine (6 mg/24 Rotigotine (8 mg/24 Placebo
49
11
62
1.2
0.9
47
11
61
1.5
2.8
48
11
61
1.2
4.8a
51
11
61
1.1
5.2a
47
11
62
1.3
181
24
62
1.3
96
24
64
1.4
215
33
61
1.4
5.0a
228
24
62
1.3
8.8a
118
24
60
1.2
h) h) h) h)
Watts et al,2 2007
Rotigotine (mean dose 5.7 mg/24 h) Placebo
Giladi et al,4 2007
Rotigotine (mean dose 7.2 mg/24 h) Ropinirole (median dose 14 mg/d) Placebo
5.3a
Treatment effect (active drug improvement minus placebo improvement; reduction 5 improvement); P.001. b Mean values. a
Table 2 Percentages of the most common adverse events reported in early and advanced Parkinson’s disease randomized, controlled, double-blind clinical trials of rotigotine Dose (mg/24 h)
Peripheral ASR Dizziness Fatigue Hallucination Headache Nausea Edema
Somnolence Vomiting
Parkinson Study Group,1 2003
Rotigotine Rotigotine Rotigotine Rotigotine Placebo
27 26 46 59 21
27 19 25 24 13
14 23 6 16 2
2 2 2 2 0
16 23 13 18 13
41 45 50 53 15
2 4 6 6 0
18 21 23 24 4
12 17 21 16 2
Watts et al,2 2007
Rotigotine mean dose (5.7) Placebo
44 12
19 13
8 5
0 1
16 9
41 17
3 3
33 20
33 20
Giladi et al,4 2007
Rotigotine mean dose (7.2) Ropinirole median dose (14) Placebo
38 7 11
14 17 10
NR NR NR
NR NR NR
10 9 8
29 36 16
NR NR NR
23 28 20
12 11 3
36 46 13
23 15 15
NR NR NR
7 14 3
10 8 8
28 24 20
9 14
